Thursday, August 26, 2010

Was the CAFE study manipulated by AstraZeneca? Maybe Not.

In Monday's post, I summarized Carl Elliott's recent article in Mother Jones, in which he argues that Dan Markingson's suicide may have been related to the fact that he was enrolled in an AstraZeneca study comparing AZ's Seroquel with two other medications. Like most clinical trials, this study put limits on what medications doctors could give their study patients. These limits are required to discover how effective a drug is for a particular condition. Otherwise, patients in research studies might be taking all kinds of miscellaneous treatments, and you wouldn't know if their improvements were due to the study drug or something else.

The crucial question here is whether this study, called the CAFE trial, was, in fact, designed to answer a valid scientific question, such as: Which of three antipsychotics is most effective? Or was it a rigged study, designed to ensure that Seroquel would look good compared to Zyprexa and Risperdal, purely in order to drive sales? It would obviously be unethical to recruit seriously ill patients into a bogus trial if it was concocted as a marketing strategy.

As Dr. Barney Carroll mentioned in a response to Monday's post, the interesting thing about the CAFE trial is that several of the major investigators were also involved in the CATIE trial. The CATIE trial was of a similar design and involved schizophrenic patients who were randomly assigned to double blind treatment with different antipsychotics. But the CATIE trial was funded by the NIMH rather than by any particular drug company. Therefore, we assume that design decisions were made relatively free of drug company input.

The results of the NIMH-funded CATIE trial were different from the AZ-funded CAFE trial--quite different. The main outcome measure for both studies was the percentage of patients who discontinued the drug. In the CAFE trial, the 12-month discontinuation rates for Zyprexa, Seroquel, and Risperdal were 68.4%, 70.9%, and 71.4%, respectively. In the CATIE trial, the18-month discontinuation rates (the 12-month rates were not reported) were 64%, 74%, and 82% for the same three drugs (two other drugs were also tested in CATIE). In the CATIE trial Zyprexa did much better than Seroquel, but it did not do better in CAFE--which seems odd considering both studies used the same methodology.

What's the explanation here? It could be simply be a statistical variation in outcomes. Perhaps CATIE's results were wrong, and perhaps CAFE's are right. After all, this is exactly why it's important to replicate a research finding. If a finding is replicated, we are much more confident in the truth of the original results.

In this case, however, the divergent results appear more likely due to the fact that in CAFE, Zyprexa and Risperdal were dosed much lower than in CATIE. Look at the table below. Zyprexa was dosed 42% lower in CAFE, Risperdal was dosed 38% lower, while Seroquel was nearly the same in the two--only 7% lower in CAFE. Thus, on the face of it, it seems clear that the CAFE study found Seroquel to be as good as Zyprexa and Risperdal because the design ensured that Seroquel would be dosed much higher than Zyprexa and Risperdal.


Drug

AZ-funded CAFE dose

NIMH-funded CATIE dose

Zyprexa

11.7 mg

20.1 mg

Risperdal

2.4 mg

3.9 mg

Seroquel

506 mg

543 mg


But why did this happen? Was this a design manipulation ordered by AstraZeneca marketing staff in order to make sure the results were to their liking? Or was it simply a research decision made with pure motives by the scientists who ran the trial? The answer to this question makes a difference. In fact, you could argue that it makes all the difference.

This post would have ended here if I hadn't emailed these questions to the researchers who designed the CAFE study, including
Dr. Joseph McEvoy, Dr. Jeffrey Lieberman, and Dr. Diana Perkins. All three of them were also involved in the CATIE trial. They reminded me of a crucial difference in the two trials, aside from the fact that one was funded by government and the other by Astra Zeneca.

The CAFE study, as should have been obvious to me by the full name ("Comparison of Atypicals in First Episode of Psychosis"), was designed with newly diagnosed patients in mind. Typically, patients with a first episode of psychosis are treated more conservatively, with lower doses of antipsychotics, as opposed to the chronic schizophrenics enrolled in the CATIE trial. So this explains why Risperdal and Zyprexa were dosed lower in CAFE than in the CATIE.

So why, you might ask, wasn't Seroquel also dosed lower? According to Dr. McEvoy, who was the co-principal investigator on both CAFE and CATIE, at that time there were no studies guiding them on Seroquel dosing in first episode patients. "Back then," he wrote me, "many argued that higher doses were needed for optimal efficacy and there was not a side effect ceiling such as risperidone has." Eventually, a study was published showing that the average Seroquel dose needed for first episode psychosis is only 268 mg/day

Dr. Lieberman, who is chair of psychiatry at Columbia University, emailed me that "Although your inferences re dosing are understandable they are entirely incorrect. The CAFE study was wholly investigator initiated and we determined the doses for each drug. There was a clear rationale for the higher quetiapine dose relative to the other drugs which I am happy to explain to you. This study design in no way was influenced adversely by industry influence."

So there you have it. If you can believe these researchers, this may have been an example of an AstraZeneca funded study without undue commercial influence. I think they are believable, and I know that Dr. Lieberman in particular has been quoted regularly in the media recently about various new drugs, and has been appropriately skeptical about their benefits over older agents.

Of course, there are other ways in which CAFE might have been rigged, which are detailed in Carl Elliott's Mother Jones article. I've asked the investigators about these allegations and will let you know if I get a response.






37 comments:

Bernard Carroll said...

Upon re-reading the CAFE report, I am struck by how the entanglement with a commercial entity has influenced the scientific agenda of these academic investigators. There is little doubt that AstraZeneca’s participation shaped the study design and the reporting. A few observations will make this clear. The main CAFE report is McEvoy JP et al American Journal of Psychiatry 2007;164:1050-1060. It helps to read it along with a companion paper: Perkins DO et al Journal of Clinical Psychiatry 2008;69:106-113.

1. AZ was the primary sponsor of the trial (see ClinicalTrials.gov).
2. AZ paid for the study.
3. Three of the named authors are AZ employees.
4. The focus was restricted to the comparison of three second generation (‘atypical’) antipsychotic drugs, excluding classical agents like perphenazine that performed so well in CATIE. This decision is pure marketing. It is like the Coke versus Pepsi ads that portray a choice as though no other options existed. This decision confirms that the study is an experimercial, designed to feature the sponsor’s drug in a market niche, which in this case is first episode psychosis.
5. The featured primary endpoint of retention over 12 months has no intuitive clinical meaning – a good number dropped out because they achieved response and disliked the medication. Not all of these discontinued against medical advice. There is no breakout of the numbers – once again the focus is not on clinical process or patient satisfaction.
6. Thus the featured primary endpoint is not an acceptable surrogate for patient improvement. In this non-inferiority trial, choosing an administrative rather than a clinical primary endpoint biases the study towards finding no difference between treatments. That would be consistent with the sponsor’s hopes.
7. There is evidence of cutting corners in patient recruitment. An unknown number of cases were enrolled with just 2 weeks duration of symptoms (see Table 1). By definition, these cases could not meet the diagnostic criteria for any of the relevant diagnoses – schizophrenia or schizoaffective disorder or schizophreniform disorder. This evidence suggests that there was pressure to achieve enrolment targets. Typically, such pressure originates with sponsors.
8. An important clinical question is whether outcomes differed by diagnosis. For instance, one might expect better improvement in cases with diagnoses of schizophreniform disorder, who comprised 29% of the full sample. No information is given on this matter. Really, clinicians would like to know.
9. Concomitant medication was used by over a quarter of the cases. However, no information is given about whether these cases overall fared better or worse than the others. The Perkins report addresses the issue of clinical predictors of dropout, and noted poor treatment response, substance abuse and depression as important factors. Really, clinicians would like to know whether adding other medications makes a difference in this population.
10. The overall rate of categorical treatment response “at some point during the study” was approximately 60% but no information was given about the timing of these responses by drug. An improvement by 12 weeks is very different from an improvement by 52 weeks. Really, clinicians would like to know how the drugs compared on this measure.
11. Finally, in resonance with my earlier comment about treating patients as commodities, there is no mention of follow-up. How many patients who discontinued after responding later relapsed, and when? How many patients received diagnostic reassignment during the 12 months of the study or later from schizophreniform to schizophrenia or from schizophrenia to bipolar disorder? These are important clinical issues that seem to have been neglected.

Bernard Carroll said...

Upon re-reading the CAFE report, I am struck by how the entanglement with a commercial entity has influenced the scientific agenda of these academic investigators. There is little doubt that AstraZeneca’s participation shaped the study design and the reporting. A few observations will make this clear. The main CAFE report is McEvoy JP et al American Journal of Psychiatry 2007;164:1050-1060. It helps to read it along with a companion paper: Perkins DO et al Journal of Clinical Psychiatry 2008;69:106-113.

1. AZ was the primary sponsor of the trial (see ClinicalTrials.gov).
2. AZ paid for the study.
3. Three of the named authors are AZ employees.
4. The focus was restricted to the comparison of three second generation (‘atypical’) antipsychotic drugs, excluding classical agents like perphenazine that performed so well in CATIE. This decision is pure marketing. It is like the Coke versus Pepsi ads that portray a choice as though no other options existed. This decision confirms that the study is an experimercial, designed to feature the sponsor’s drug in a market niche, which in this case is first episode psychosis.
5. The featured primary endpoint of retention over 12 months has no intuitive clinical meaning – a good number dropped out because they achieved response and disliked the medication. Not all of these discontinued against medical advice. There is no breakout of the numbers – once again the focus is not on clinical process or patient satisfaction.
6. Thus the featured primary endpoint is not an acceptable surrogate for patient improvement. In this non-inferiority trial, choosing an administrative rather than a clinical primary endpoint biases the study towards finding no difference between treatments. That would be consistent with the sponsor’s hopes.
7. There is evidence of cutting corners in patient recruitment. An unknown number of cases were enrolled with just 2 weeks duration of symptoms (see Table 1). By definition, these cases could not meet the diagnostic criteria for any of the relevant diagnoses – schizophrenia or schizoaffective disorder or schizophreniform disorder. This evidence suggests that there was pressure to achieve enrolment targets. Typically, such pressure originates with sponsors.
8. An important clinical question is whether outcomes differed by diagnosis. For instance, one might expect better improvement in cases with diagnoses of schizophreniform disorder, who comprised 29% of the full sample. No information is given on this matter. Really, clinicians would like to know.
9. Concomitant medication was used by over a quarter of the cases. However, no information is given about whether these cases overall fared better or worse than the others. The Perkins report addresses the issue of clinical predictors of dropout, and noted poor treatment response, substance abuse and depression as important factors. Really, clinicians would like to know whether adding other medications makes a difference in this population.
10. The overall rate of categorical treatment response “at some point during the study” was approximately 60% but no information was given about the timing of these responses by drug. An improvement by 12 weeks is very different from an improvement by 52 weeks. Really, clinicians would like to know how the drugs compared on this measure.
11. Finally, in resonance with my earlier comment about treating patients as commodities, there is no mention of follow-up. How many patients who discontinued after responding later relapsed, and when? How many patients received diagnostic reassignment during the 12 months of the study or later from schizophreniform to schizophrenia or from schizophrenia to bipolar disorder? These are important clinical issues that seem to have been neglected.

Joel Hassman, MD said...

You know what, someone has to go out on the proverbial limb and call Astra Zeneca for what their agenda has been since 2000--pushing the ceiling too high!!!

I go to a drug dinner, my last I think, to hear this doc from Chicago talk of how you can easily go to 1000mg and most patients tolerate it. Well, I was not well received in challenging it the room, and the honeymoon was over for me to look to Seroquel as a medication thereafter, especially when the anxiolytic agenda was revealed about two years ago!

Docs know what are equivalent doses for what diagnosis we are applying antipsychotics for, and for these drug companies to be so bold and flagrantly manipulative to do otherwise is, well, disgusting!

So, as you know well from me, no sugar coating here! And do not get me started on Bristol Myers marketing campaign regarding Abilify! And to push more than 10mg as an adjunct, !?!?.

But, another story, another time. Enjoy this weekend in New England, I know I will!!!

Anonymous said...

All I know is that whenever Nemeroff was outed for his less than stellar ethics regarding his Pharma reporting, Lieberman was always quoted as a defender of Chuckie's reputation. Go figure.

Neuroskeptic said...

"The CAFE study was wholly investigator initiated and we determined the doses for each drug. There was a clear rationale for the higher quetiapine dose relative to the other drugs which I am happy to explain to you."

Whatever the rationale, and we have no way of knowing, after the fact, what the investigators were thinking - shouldn't this trial have been called "Comparison of Low Dose Atypicals vs. High Dose Quetiapine in First Episode Psychosis"?

Not quite as catchy as CAFE I admit...

Uma said...

The comment by Bernard Carroll really opened my eyes. At the end of this study, nobody asked if patients got any better! It was simply not a criterion. All they care about is reverse engineering the findings. oh my!! The plot gets thicker and murkier....

Carl Elliott said...

The dosing disparities are striking, but manipulating doses is a fairly crude way of rigging a study. The critics I quoted in the Mother Jones article had different concerns: the small sample size, which was unlikely to show a difference between the three drugs; the outcome measure -- "all-cause treatment discontinuation," with no explanation why patients were choosing to stop taking their drugs; and the failure to include a first-generation antipsychotic as a control drug. AstraZeneca had already conducted a study in which Seroquel had performed worse than Haldol, and the unsealed litigation documents make it clear that the company was trying to find ways to spin or bury that study.

The 2006 AJP article by Heres, Davis, et al that I cited -- "Why olanzapine beats risperidone, risperidone beats quetiapine, and quetiapine beats olanzapine" -- found that 90% of industry-sponsored trials of atypicals came out in favor of the sponsor's drugs. It is worth noting that three of the biased publications examined in that study came from AstraZeneca.

As to the claim that this study was completely "investigator-initiated: the phrase "investigator-initiated" loses some of its meaning when three of the investigators named as authors are AstraZeneca employees, and four others are paid AstraZeneca consultants.

I would like to know why the investigators who initiated this study decided not to exclude patients at risk of homicide or violence. Among the adverse events listed in the AJP report was one "alleged homicide." It would be useful to know more about this homicide. Of course, Dan Markingson was also recruited into the study despite having been involuntarily committed for threatening homicide. Was the decision to include potentially homicidal subjects an oversight, or a deliberate decision?

The AJP report on the CAFE study also includes this questionable statement: that two suicides occurred in the CAFE study "despite the close attention provided in clinical aftercare programs." As I hope my article has made clear, there was no such "close attention" provided to Dan Markingson, or else he would still be alive.

Sara said...

To me, the first sentence of the CAFE study is very revealing, "Patients experiencing a first episode of psychosis have a better therapeutic response to antipsychotic medications than do chronic, multiepsiode patients." Well, by golly -- what I want to know is whether patients who have a first episode of psychosis have a better chance of getting better over the long term if they are given antipsychotics (and then left on them for 52+ weeks besides) or not. Let's compare patients who are given antipsychotics for a first episode with those who aren't. That's the important issue. These guys are off base before they even start. In a way my mind just boggles that clinicians and scientists don't see this. They are so brain washed by that immediate sedating effect of these meds and the "benefit" that brings that they don't see anything beyond that. The big picture is completely lost. I think it's a disgrace.

Alex Pirie said...

I coordinate health studies and health care information through an immigrant health networking group and a major concern among the parents in the communities we serve revolves around the use of psychotropic medications. I can't tell you how much we appreciate your dogged asking of tough and discomforting questions and your diligence in ferreting out the answers. Thanks!

Anonymous said...

Uma,

They never care.

G Spielmans said...

I don't know the motivations of the individual CAFE investigators. However, I do know that internal AstraZeneca documents show that the company had data which indicated that the first-generation antipsychotic drug haloperidol worked better than Seroquel on measures of schizophrenia symptoms. AstraZeneca did its best to keep such information hidden. More details on this and other related items can be found in this article.

Since AZ was aware that Seroquel performed worse than Haldol across multiple trials, there was a good reason for AZ to not include a first-generation antipsychotic in CAFE.

If AZ really had no role in designing this study, then I wonder why the independent investigators would not have been curious about how an older drug would have compared to the newer medications.

Dr. Carroll's lengthy critique about the study's methods should be read thoroughly when interpreting the results of CAFE. But even if this study were perfectly designed, the ethical lapses raised in Dr. Elliott's article would still be far beyond appalling.

Sara said...

Interesting article by The Last Psychiatrist on low vs. high doses of Seroquel. Not the linear progression you might expect and could be relevant to this study. You will have to copy and paste the link.

http://thelastpsychiatrist.com/2007/07/
the_most_important_article_on.html

And I agree that Dr. Carroll brings up many good points about the study overall. I wouldn't have put it as graciously as he does. Relevant patient outcomes, to say nothing of actual improved well being, were routinely ignored and dismissed.

John M. Nard MD said...

The Study: At week 52, all-cause treatment discontinuation rates were 68.4%, 70.9%, and 71.4% for olanzapine, quetiapine, and risperidone, respectively...
CONCLUSIONS: Olanzapine, quetiapine, and risperidone demonstrated comparable effectiveness in early-psychosis patients, as indicated by similar rates of all-cause treatment discontinuation.

Dr. Carroll makes the obvious point above that "The featured primary endpoint of retention over 12 months has no intuitive clinical meaning." But more than that, in "Making a Killing", Dr. Elliot's article about Dan Markingson who ws in that study, we read: "After Dan was enrolled, he stayed at Fairview for about two more weeks. By that point, Olson thought Dan’s symptoms were under control, but Mary was still very worried by his erratic behavior. She recalls meeting with the doctor: “Olson came in and sat down and opened his file and said, ‘Oh, Dan is doing so well.’ And I said, ‘No, Dr. Olson, Dan is not doing well.’ I think he was taken aback.” Even so, on December 8, 2003, Dan was transferred to Theo House, a halfway house in St. Paul. He was required to sign an agreement confirming that he understood he could be involuntarily committed if he didn’t continue taking his medication and keeping his cafe study appointments."

Am I misreading something? How can a study use an outcome like "all-cause treatment discontinuation" when people in the study are threatened with commitment if they discontinue their medication?

In the tragic case on Dan Markingson, he didn't discontinue his medicine, he discontinued his life [while floridly psychotic]. But until the time of his death he was a treatment success? What folly...

Uma said...

About the dosing disparities:
Let me give you an example from my own life. I have a choice of 2 meds for my disorder (hyperprolactinemia). I take 2.5 mg bromocriptin daily and it can be replaced by 0.5 mg cabergolin every other day (which works out to a tenth of the bromocriptin). Both are said to have the same effect in lowering my prolactin levels. so...isn't this an established fact that dosages don't have to be the same? If I increase the cabergolin or decrease the bromocriptin to a tenth, then bromocriptin will come out as ineffective! I actually prefer bromocriptin as it's cheaper. But when I have an upset tummy I take caberlin. I have also read that bromocriptin is more effective with shrinking small pituitary tumors (which I do have) as compared to cabergolin. So anyways....Dr Carlat you seem to be barking up the wrong tree.

Uma said...
This comment has been removed by the author.
Uma said...

what I don't get is, once they have FDA approval why don't they proceed to convert as many doctors as they can (with money) instead of funding universities to prove their lies? or just get Oprah to invite teary eyed happy patients who want to share incredible stories of recovery...
(don't mind my comments, I am nuts)

mike howard said...

I remember well the first published reference on the Cafe study. "Landmark Study Indicates Equivalent Effectiveness of Atypical Antipsychotics in the Treatment of First-Episode Psychosis" from exotic Vienna, Austria, at the 8th World Congress of Biological Psychiatry. The study, known as CAFE(Comparison of Atypicals in First Episode Psychosis), is the first to examine the comparative effects of these three agents in this setting and provides clinicians with valuable insight into how to optimize atypical antipsychotic treatment in this important patient population.

Now, there you have it. We should now have thousands of "clinicians" world wide knowing exactly how to optimize treatment for all their first episode patients. I guess it's a little scary to even think that before CAFE came out our "clinicians" had no idea on how to treat first episode psychosis patients. The drugs had only been on the market for let's say 5-10 years. Again, that's a little scary for me as a consumer, one can only hope that if you ever need treatment for your first episode, you better hope that your "clinician" reads all the current first episode data. Sorry, if CAFE meant anything beyond marketing Seroquel, there would have had numerous follow up studies then and still now. Guess what? checked with Pubmed and that doesn't seem to be the case. AstraZeneca got what they wanted and paid for, there own bragging rights. Carl Elliott could not have been more accurate. Dr.s McEvoy and Lieberman are never far from the publicity and money, they often leave quite a paper trial, the real problem for me is, I don't believe them. Read a few of the internal e-mails regarding McEvoy and CAFE, and quickly came to the judgment that it was recruit, recruit, recruit at all costs. In the six years since Dan Markingson died, NOTHING has changed with how first episode patients are treated based on the results from the CAFE study. AstraZeneca knew all along that in CATIE they would not fair very well. So they devised CAFE to run concurrently so they could at least manipulate those results. In an era of Conflict-of-Interest popping up everywhere with these so-called researchers, does anyone else question why and how Lieberman and McEvoy and almost all the CAFE site investigators were also doing CATIE? One last thing, Bernard Carroll has it right, is there really such a thing as a first episode diagnosis within two weeks of symptoms? The reason of course is simple, it's marketing. Get em early and keep them late.

mike howard said...

The definition of insanity applies to anyone trying to accurately disseminate the data from the CAFE study. Doing the same thing over and over again in the same way but expecting different results. McEvoy and Lieberman were/are paid by AstraZeneca to produce marketable results. End of that story. How is it that these drugs had already been on the market for years before CAFE came along; are we to believe that treating clinicians had no clue on how to use and dose them? AstraZeneca knew that if the CATIE results held true they would not look good; therefore, CAFE was designed so Zeneca could 'manage' the results and control bragging rights. And what has changed in the 5 years since CAFE ended, absolutely nothing. I really seriously doubt that any treating clinician looks up and refers to the landmark CAFE study when facing a first episode patient.

mary weiss said...

Dr. Carlat,

In your blog you leave room for the possibility that perhaps the study was designed with no ulterior motives by AstraZeneca. I ask, are you going to exhibit the same 'open-mindedness' another dozen years from now when these drugs will have been on the market for a quarter century? How can it be that a simply layman such as myself, whose initial confrontation with these drugs was the death of my son Dan, understand simple marketing better than you, a well-educated, learned doctor? Do you really believe that these pharmaceutical companies and their 'doctors' are driven by altruism and not pure greed?
Dr. Jeffrey Lieberman in the Washington Post 10/3/06 said, as an explanation for the dismal results of these drugs: "The claims of superiority for the [newer drugs] were greatly exaggerated...the aggressive marketing of these drugs may have contribtued to this enhanced perception of their effectiveness..." Very succinctly put, not open to misinterpretation!
Your comments prompt me to put you on the lefthand side of my balance sheet, with Lieberman, Nemeroff, Garfinkel, olson, schulz, etal.

Mary Weiss

P.S. You call a dose of 506 mg. Seroquel high? Dan was given 800 mg - and not because he needed it! At one point, olson left instructions for Dan's dosage to be increased, and then for it to be increased 3 days after that without seeing him!!

Uma said...
This comment has been removed by the author.
Uma said...

@Dr Carlat (wrt Mary Weiss' comment) This was a double bind study and Dan's psychiatrist was not supposed to know what Dan was on...so how did he know the dosage? or did he increase the dosage without knowing what drug Dan was being given? Did he know the actual dosage Dan was taking? Or did he increase the dosage without knowing the dosage of the unknown drug?

John M. Nardo MD said...

To Mary Weiss,

I appreciate your comments here and on Stephany's blog. It's encouraging to have the voices of people directly impacted by these Pharmatrocities in the mix. It helps keep the focus where it needs to be - on the clinical care of patients...

Keep talking...

Joel Hassman, MD said...

Hmmm, I guess Ms Weiss called you on her interpretation of this blog posting. You did not post my last comment I submitted to this thread on Friday night, because it was, what, too harsh on Astra Zeneca's behaviors? I do not know if you work in any kind of community mental health clinic or service, but believe me, Seroquel gets written like pez by a good many providers, and at dosages outside psychosis that would give some pause if you equated it to use of Risperdal or Zyprexa.

Are you willing to go on record for what you would write for treating anxiety with Seroquel, and do so as a solo med?

I will: never as a solo, rarely as an intervention, and if exhausted more reasonable choices, maybe use 25 to 100mg max, and not interested in XR.

Interesting AZ has basically eliminated 25mg as a dose of consideration. Because insurers expect you to split 50mg, or, they (AZ) didn't make XR in this dose and doesn't want providers to think about it when Seroquel IR loses patent!?

gewisn said...

I choose to interpret Dr Carlat's interpretation thusly:
He simply forgot to include the rolling eyes emoticon. Maybe even the wink. His conclusion, "There you have it," was sarcastic.
And he let the rest of us supply the anti-Pharma rant.

If I'm wrong, PLEASE don't tell me.

Daniel Carlat, M.D. said...

Many good points have been raised here. I have no great love for either Seroquel or AstraZeneca. Seroquel is a good antipsychotic but no better than the others. It causes more weight gain than most, and causes profound sedation, which can be a positive for some patients but a negative for many. I've called AstraZeneca out for its bad behavior more than once on this blog.

However, it's important not to paint every AstraZeneca study with the same broad brush of accusation. I give AZ some credit for sponsoring a study comparing Seroquel with two other atypicals. They could have just left their efforts at placebo controlled trials and called it a day. The fact that Seroquel ended up being dosed at roughly double the required dose rightfully arouses suspicion. The investigators claim that dosing decision was made independently of the company's input. You can call them liars if you want, but there's no evidence to support that supposition.

That said, I have no doubt that the CAFE study was manipulated in some ways for promotional intent--for example, the choice to omit a conventional antipsychotic from the trial seems odd, especially since these same investigators pushed hard to include a conventional in the CATIE trial. My guess is that Dr. Lieberman or one of the other investigators brought up the idea of including a conventional and that it was shot down by somebody with AZ, most likely on the grounds that it would be too hard to recruit enough patients to populate a fourth arm of the trial. You can argue that this was a legitimate decision, but it is convenient that this and other design decisions ended up benefitting the sponsor's drug sales.

Ultimately, Dr. Lieberman and his CAFE colleagues are suffering a credibility gap, but it is not necessarily of their own making. There are plenty of researchers in psychiatry who are in it because they care about patients, and who genuinely want to find a cure for mental illness. In fact, the majority of researchers who I have come to know would fit that profile.

The worst actors tend to be the lower tier hired guns, those who are not passionate enough about research to make a successful career out of it.

Regarding the specific points that many commenters have discussed, they are legitimate questions, and I would hope the CAFE investigators might see fit to respond to them here.

mike howard said...

Dr Carlat--- I think Lieberman and McEvoy better get their facts straight. I personally have a copy of the protocol for the CAFE study and on pages 13-14 it discusses the dosing design. By day 7,8 the recommended dose of study drug is 2capsules AM and 2capsulespm. Someone on seroquel therefore would be receiving 400mg a day by day 8. And from then on it's up to the investigator and their decision on how high to dose based on the subjects tolerability and clinical response. And contrary to what McEvoy stated regarding no reference on first episode , it says right on the same pages that the dosing range takes into account that first episode patients , compared to chronic patients, usually respond to lower doses of antipsychotic medication , and will be more likely to develop adverse effects if the highest dose range is used. etc-etc-etc. Be more than happy to give you a copy if you have not already read it.

Evelyn Pringle said...

American consumers should count themselves very lucky that highly qualified and busy professionals such as Dr Carroll (and more recently others), will put in the time it takes to track all the corrupt academics on the take from the drug makers and warn us about the rigged studies.

While the highly paid quacks rake in millions from Pharma (much of it undisclosed until recently), they get paid nothing for their efforts. Plus they stand a good chance of having their reputations attacked mercilessly.

Hardly an incentive to keep at it - but Dr Carroll obviously can not be deterred.

mary weiss said...

Dr. Carlat,

In your blog you state, "the worst actors tend to be the lower tier hired guns who are not passionate enough about research to make a successful career of it."

Dr. Carlat, is Dr. Joseph Biederman of Harvard, who received 1.6 mllion from drug companies from 2006-2007 in this 'lower tier'? Is Dr. Melissa del Bello of the University of Cincinnati, who received $100,000 from AZ in 2003, and $238,000 from 2005-2007 from AZ also in this 'lower tier'? What about Minnesota psychiatrist George Realmuto who said "Academics don't get paid very much. If I were an entertainer, I think I would certainly do a lot better." (hey! me too!)Or Dr. John Simon, another Minnesota 'actor' who said "most of the doctors who are really good have ties to [the drug] industry." Lower tier? That begs the question, Dr. Carlat, what is the definition nowadays of a really good doctor?

In my book it is Bernard Carroll, who is truly passionate about the truth - not these so-called doctors (who probably never cured anyone of anything) whose only interest is the condition of their bank account - not the condition of their patient. And believe me, I speak from experience!

So don't even try to imply that psychiatry has not been taken over by greed!

And you can read my book, "A Mother's Sorrow" to learn more of the truth!

Mary Weiss, mother of Dan

Stephany said...

I find it hard to comprehend that the UMN is currently trialing Seroquel XR for BPD, sponsored by AstraZeneca and principal investigator is Dr.Charles Schulz.

Once COI happens is it not a red flag for a study such as this one, which is only being trialed against a placebo?

I appreciate reading all of the comments here and the professionals speaking out alongside Mary Weiss is refreshing, to say the least, actually I say thanks.



Stephany

mike howard said...

One last observation on the great CAFE study and these so-called great researchers/scientists. The entire time that AZ was running the CAFE study they were also running Seroquel XR studies at many of the same academic instutions, including the University of Minnesota. Now with the big push and advertising geared toward Seroquel XR it just adds that much more credibility to the fact that CAFE meant nothing. The starting dose for XR is not the same as regular Seroquel, nor is it increased or decreased at the same level. There was absolutely no reason to have done the CAFE study except for marketing reasons. Pure and simple. It's really sad, but the average American citizen has no idea that psychiatry is nothing but handing out a pill. When has McEvoy or Liberman ever stood up in front of a group of their peers at some CME (of course paid for by pharma) and stated that the results of some clinical trial certainly don't match up with whats being reported to the FDA through their adverse event reporting system. That some 6 weeks trial data don't carryover in the real world. Truth is for hire and we all should know that pharma money buys truth. "The world is a dangerous place to live, not because of evil people, but because ordinary people do nothing about it." (Albert Einstein)

SteveM said...

Re: Dr Carlat: "[Seroquel] causes profound sedation, which can be a positive for some patients but a negative for many."

Evidently Seroquel is being administered as a chemical sledge hammer to treat PTSD related insomnia:

http://www.pharmalot.com/2010/08/the-military-post-traumatic-stress-and-seroquel/

Risking Akathesia, Tardive Dyskinesia and Metabolic Syndrome to put a guy to sleep? That's almost "Cuckoo's Nest" stuff. Why should Congress need to investigate? What the heck is going on with the doctors prescribing Seroquel in the first place when there are a plethora of less dangerous sleep aid alternatives?

I'm not a physician. But I don't get it.

BTW, from the link:

"Seroquel is now the VA’s second-biggest prescription drug expenditure since 2007, behind the Plavix bloodthinner. The agency spent $125.4 million last fiscal year on Seroquel, up from $14.4 million in 2001

That's a lot of insanity...

Joel Hassman, MD said...

Mary Weiss is right, although I would not say it is a majority of our colleagues, it is a sizeable minority who have sold out and made us guilty by association. The fact that so many alleged "KOLs" have exhibited what is clearly clouded, if not downright corrupt judgments in aligning with the pharmaceutical organizations that have literally made a killing in our field, hence the title of the article you have spotlighted, we look bad by not refuting these people outwardly.

Aren't you tired of this fraternity attitude among us, especially the older colleagues? This is not a country club, this is health care, we took an oath to treat people and do it right and responsibly, and yet the APA, in Joel Hassman's opinion, is a joke year in and out per the people elected that represent the organization.

I honestly do not know how people of principle and integrity belong to the APA as long as the leadership that is stays in place. Harold Eist was the last person I felt spoke for me as a leader, and that is why I left when he did.

You colleagues who come here to read these posts and threads, what do you really believe in? Is psychiatry really just a biochemical intervention by in large, or, do you have an alternate philosophy that you are tired of watching it run over and over by narrow minded individuals, who, at the end of the day, really are not in touch with the principles of being a doctor?

17 years I have been a psychiatrist, and I continue to wonder of late whether I was sold out by my alleged mentors and leaders. But, I like helping people, so, I won't succumb to these "colleagues" who left their souls at the bank!!!

Dr John said...

I don't think most of the MD's who read this blog buy into the reductive simplicity of biological psychiatry. That fact that they read this blog at all likely means they are unhappy with the current state of affairs in their profession. (Either that or they are happy but want to keep tabs on the subversives within their field).Psychiatry certainly is not alone in it's corrupt embrace of big pharma and its money. We are just the worst offenders because we are the easiest to corrupt in the world of medicine.

We have no coherent models of pathology unlike other areas of medicine.We deal in wishy washy constructs who's definitions may change from DSM to DSM based upon politics and fad as apposed to real scientific understanding. Offering descriptions of descriptions (MDD, ADHD,Schizophrenia) is not science and it certainly is not really knowing anything. Big Pharma swept in with its money and provided the chance for us all to hold our nose, look the other way and claim scientific legitimacy while standing on a pile of junk science and myth. "look everyone at my diploma as I bestow on you the knowledge that only a Dr knows when you have a chemical imbalance but don't ask me how I know".

During all my training I can not really recall a strong voice of dissent as to the selling and distribution of this myth. I got different perspectives from analysts or behaviorists or even social workers but not even those people would stand up and say all of this is a pant load and its bad for pts. These were not bad or stupid people either. The fact is we tend to believe weird things for complex reasons and rarely question what those in charge tell us. The best you could hope for was for someone to mock genuflect at the alter of the "biopsychosocial model" on the way to the feeding trough that pharma provided them.

The truth that we as clinicians don't have any real knowledge that is compelling and works in the way that knowledge about a Gram negative infection or an MI does is just too scary for those on top who are invested in all of this to admit. To do so means you have to question the very paradigm you are producing work in. I do not think you need to be Kuhn to recognize this alsmost never happens. I think as Dr Hassman implies, it does not prevent us from being humble and trying to help people with great care. We just should not be holding our breath waiting for the APA, AZ or the authors of the CAFE report to shine much light to lead us out of the hole we have fallen into.

Uma said...
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Anonymous said...

It is so ironic that after selling our souls to the drug companies, they are now abandoning us! They have had it with Psychiatry. They made their money marketing the chemical imbalance nonsense, and now that their medicines have been exposed as almost no better than placebo (antidepressants), and certainly no better than first line agents (antipsychotics and antidepressants), just with different side effects, they are focusing on dementia drug development. Sure, they will alter a molecule here and there and market a "new" and "blockbuster" antidepressant, but it won't really be "new" in any meaningful sense and it most certainly won't be a blockbuster, unless, of course, we psychiatrists continue to corrupt ourselves and act as drug reps! Like we have done for the past 30 years.

Sara said...

Dr. John, I share your views and think you express them magnificently. Great writing.

Anonymous said...

My thoughts mirror Dr. John's last comment. Like any profession there is vested interest not only financially, but also in ego.

Much of my experience observing patients over the past decade again just reiterates some of the active ingredient studies (that big pharma doesn't do) showing the physical side effects help a person to believe in the positive drug effect. The Atypicals have such a strong sedative affect upon a person, that they can't help but to believe that it is powerful. I've had many children complain about always feeling sleepy, but many of those in power--parents/grouphomes/school etc. all usually want this effect.

Many of the times I don't understand why they just don't give some of the unruly kids sleeping pills--its hard to act out or show any behavioral manifestations when your unconscious right? In another five years or so when all these kids that have been heavily dosed with atypicals start getting diabetes, tardive, or N.M.S. and the lawsuits start coming in...perhaps this soft science and sedating children 'off label' will be seen as what it really is, those in power chemically abusing children who aren't psychotic. I mean i've seen children who just have ADHD many times given atypicals to basically make it so they can sleep because they are so amped up. It's a sad joke, and if this was being done to adults en masse--particularly savvy consumers with resources--this wouldn't be happening at this level, it would be small numbers of people being given medications with dangerous and potentially fatal side effects.

-Mitch